Cytokines are secreted regulators that control the production, maturation and functional activation of blood cells that are essential for hemostasia and host defense from infection. These beneficial actions of cytokines have been harnessed clinically, for example the use of G-CSF to promote recovery of white blood cells in patients receiving cancer chemotherapy, or EPO to treat anemia. In addition, deregulation of cytokines, their receptors or intracellular signal transduction pathways is associated with autoimmunity and cancer. The importance of negative regulation of cytokine signaling cascades has come clearly into focus with our identification and characterization of the family of Suppressors of Cytokine Signaling (SOCS) proteins. Our long-term objective is to identify the specific cytokines regulated by individual SOCS proteins and the cells and biological systems dependent on SOCS regulation. We seek to define the biochemical basis of SOCS action via elucidation of the structures of, and physical interactions between, SOCS proteins and the signaling machinery and to define the disease contexts in which manipulation of SOCS proteins may prove clinically beneficial. Our focus here is on S0CS3, the key negative regulator of G-CSF and IL-6 that is required to prevent spontaneous inflammatory disease. Applying a multidlsciplinary approach employing biochemical and structural biological tools, cell biology and genetically modified mouse models, our major goals are: defining the specific roles of S0CS3 in relevant mouse models of inflammation and hematopoietic malignancy, understanding the shared or overlapping physiological roles of S0CS3 with other SOCS family members, and defining the functions of protein domains within the overall actions of S0CS3, along with discovery of novel protein targets of S0CS3 action. RELEVANCE (See instructions): Successful outcomes will provide new strategies for intervention in cytokine-related diseases, particularly cancer and inflammation.